Chronic glomerulonephritis is associated with progressive kidney disease in adults and adolescents. In glomerular disorders, high amounts of protein particularly albumin pass through the damaged glomerular filtration barrier. It has long been established that proteinuria is detrimental to kidneys and patients with heavy proteinuria show a rapid deterioration of their renal function. In the previous studies, the candidate showed that high concentrations of albumin, above the reabsorptive capacity of the proximal tubule cells, mimicking the nephrotic milieu result in apoptosis. Endocytosis of proteins and nutrients in the proximal tubule is regulated by a highly sophisticated machinery containing clathrin, receptors and adaptor proteins. The best described receptor-adaptor protein complex in the proximal tubule is megalin-disabled-2 (Dab2). Dab2 is also implicated in signal transduction events regulating cell proliferation and differentiation. The candidate proposes that there is an overlap between endocytosis and cell signaling event that mediate albumin induced apoptosis. Preliminary studies showed an interaction between the survival factor protein kinase B (PKB/Akt) and endocytic adaptor protein Dab2. The down regulation of this interaction associated with albumin-induced apoptosis allowed us to hypothesize that Dab2 is a key adaptor protein that regulates both apoptosis and endocytosis. The goal of this project is to elucidate the mechanism and implications of this interaction to cell survival. Thus in aim 1, the candidate will investigate the role of albumin endocytosis on Dab2-PKB interaction and the fate/trafficking of megalin/Dab2 with albumin overload. In aim 2, the candidate will study the role of Dab2 in albumin-induced apoptosis and the nature of Dab2-PKB interaction. Short-term goal of the candidate is to acquire further training that will enable her to learn the state-of-art cell biology techniques such as cloning, protein-protein interactions and confocal imaging under the guidance of her mentor Dr.Linton Traub. The long term objective is to discover therapeutic interventions that will halt the proteinuria induced progression of glomerular disease by investigating the molecular network of events that are associated with proximal tubule injury and albumin endocytosis. PUBLIC HEALTH RELEVANCE: Chronic glomerulonephritis is an important problem with high morbidity resulting in chronic renal failure. The degree of proteinuria correlates with the rate of progression. The main goal of this project is to dissect the mechanism of proteinuria induced kidney damage in an attempt to develop preventive strategies to halt progression of glomerular diseases.